CA1113943A - Thiazolidine derivative - Google Patents
Thiazolidine derivativeInfo
- Publication number
- CA1113943A CA1113943A CA312,770A CA312770A CA1113943A CA 1113943 A CA1113943 A CA 1113943A CA 312770 A CA312770 A CA 312770A CA 1113943 A CA1113943 A CA 1113943A
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- Prior art keywords
- compound
- angiotensin
- mercapto
- acid
- methylpropanoyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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Abstract
ABSTRACT OF THE DISCLOSURE
This invention discloses (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid of the formula
This invention discloses (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid of the formula
Description
~L3L353~3 1 This invention relates to ~4R)-3-[(2S) 3-mercapto-2-methylpropanoyl]-4-thiazolindinecarboxylic acid represented by the formula (I):
S
CH3 ~ ~ <
~S ~ ~C0~ ~O`H
position comprising of the same. The compound (I) of this inven-tion has an inhibitory acitivity against angiotensin I-converting enzyme and produces a potent antihypertensive action on the renal hypertensive rats. The onset of the compound (I) is rapid after oral administration due to its high lipophilic property. More-over, the compound has less undesirable adverse effects such as enhancement of carragenin-induced edema and of bradykinin-induced nociception in rats.
The compound of this invention is synthesized by the ;
following method.
S-Benzoyl-3-mercapto-2-methylpropanoyl halide represented by the formula (II); C6H5COSCH2CH(CH3)COX wherein X is halogen atom, is reacted with (4R)~thiazolidinecarboxylic acid by a known method such as Schotten-Baumann reaction to obtain (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidine-carboxylic acid. The resulting compound is debenzoylated with heating, if necessary, under the presence of acid or alkali. As ;
the acid for the reaction, inorganic or organic acid such as hydrochloric acid, sulfuric acid, phosphoric zcid and p-toluene-sulfonic acid may be used. As the alkali, hydroxide of alkaline metals and alkaline earth metals such as sodium hydroxide, potassium hydroxide and calcium hydroxide, or ammonia may be used. As the solvent, the organlc solvent or aqueous organic 1 solvent which is not concerned to the reaction may be used. As the solvent which is not concerned to the reaction, lower alcohol such as methanol, ethanol, n-propanol, isopropanol and t-butanol, acetone, tetrahydrofuran, or dioxane may be used. The debenzoylation is well known as ammonolysis in using aqueous ammonia. The reaction is carried out at xoom temperature, with ice-cooling, or with heating. The objective compound is isolated as follows~ The reaction solution containng the objective compound obtained by hyd~olysis is concentrated, iE necessary, cooled and acidified to crystallize the objective compound. If necessary, the compound is extracted with organic solvent such as ethyl acetate, and the organic layer is dehydrated and Concentrated. The obtained compound is purified with the proper solvent such as ethyl acetate and benzene.
EXAMPLE
(4R)-3-[(2S)-3-Mercapto-2-methylpropanoyl]-4-thiazolidine-=- carboxylic acid a) 6.7 g of (4R)-4-thiazolidinecarboxylic acid and 12.6 g of sodium bicarbonate are dissolved in 150 ml of water. To ~his solution, 12.1 g o~ S-benzoyl-3-mercapto-2-methylpropanoyl chloride is added with stirring under ice-coolingO After the addition, the mixture is stirred for 1 hour under ice-cooling and acidified with dilute hydrochloric acid to obtain oil~ The oil is extracted with ethyl acetate,and the ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. To the oil thus obtained, 100 ml of ether is added to obtain crystalsO The crystals are filtered to obtain (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid, yield 5.0 g (29~), mp. 137-139C
(benzene), [~]25 -172.4C (c=l, methanol).
~ ~L3~d~3 Anal. Calc~ for C15H17N04S2: C, 53.08; H, 5.05; N, 4.13.
Found: C, 53.21; H, 5-00; N, 4.19.
Dicyclohexylamine salt mp. 199-200C (ethyl acetate-ethanol) [d]25 -109.9C (c=l~methanol) Anal Calcd. for Cl5Hl7No4s2 C12 23 N, 5.38.
Found: C, 62.32; H, 7.73; N, 5.40.
b) By substituting (2S)-S-benzoyl-3-mercapto-2-methylpropanoyl chloride [[~]25 -37.6 (c=l.0, chloroform)], which is prepared from (2S)-S-benzoyl-3-mercapto-2-methylpropanoic acid [mp.
6~-71C, [~]~5-40.4 lc=2.0, methanol)] and thionyl chloride by known method, for S-benzoyl-3-mercapto-2-methylpropanoyl chloride in the procedure of a~ove a), (4R)-3-[(2S~-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid is obtained, yield 14.1 g (83%), mp. 137-139C (benzene).
: c~ To 2.0 g of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methyl-propanoyl]-4-thiazolidinecarboxylic acid, 20 ml of conc. ammo~ia is added and stirred at room temperature for 1 hour. The excess ammonia is removed by concentration in vacuo and by-product, benzamide, is extracted with ethyl acetate. The water layer is acidified with dilute hydrochloric acid and the produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to obtain (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl~-4-thiazolidinecarboxylic acid, mp. 113-114C
(ether), yield 1.0 g ~72%), [d]25-172.0 (c=l, methanol).
Anal- Calcd- for C8H13N3S2 C~ 40-83; H~ 5-57; N~ 5-95-Found: C, 40. 94; H, 5.54; N, 5.94.
Dicyclohexylamine salt 3~43 1 mp- 190-191C (ethyl aceta-te) [~]25-116.1 (c=l, methanol) Anal- Calcd- for C8H13N3S2 C12H23 Found: C, 57~63; H, 8.70; N, 6.70.
Reference Example a) The filtrate of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methyl-propanoyl]-4-thiazolidinecarboxylic acid in EXAMPIE a) is concentrated to dryness to obtain oil. The oil is applied to silica gel chromatography to obtain (4R)-3-[(2R)-S-benæoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid, yield ~ [o~25 19 5 (c=l, methanol).
Dicyclohexylamine salt mp. 140-141C (ethyl acetate~
[~]D5-53.2O (c=l, methanol).
Anal. Calcd- for ClsH17NO4S2 C12H23 N, 5.38.
:` Found: C, 62.27; H, 7.70; N, 5.36.
b) To 2.0 g of (4R)-3-[(2R)-S-benzoyl-3-mercapto-2-methyl-propanoyl]-4-thiazolidinecarboxylic acid, 20 ml of conc.
ammonia is added and treated in the same manner as mentioned above to obtain (4R)-3-[(2R)-3~mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid, yield 0.8 g (58~), [~]25-81.5 (c=l, methanol).
Dicyclohexylamine salt mp. 179-180C (ethyl acetate-ethanol) [d] 25-84. 5 (c-l, methanol) Anal. Calcd. for C8Hl3No3s2~cl2H23N C,57 66; EII 8-71; N~ 6-72-Found: C, 57.60; H, 8.74; N, 6.70.
The potent antihypertensive effect of the compound and salts of this invention is clear; that is, the inhibitor of ~3~43 1 an~iotensin I-coverting enzyrne which converts biologically inactive decapeptide, angiotensin I, to active octapeptide, angiotensin II, is ~ound to be useful as an antihypertensive medicine~R.L. Soffer, 1976; M.A. Ondetti, et al. 1977). In view of the above, we investigated the pharmacological activities of the present antih~pertènsive agent from the aspect of inhibitory activity against the enzyme.
As the method of measurement of angiotensin I-conver-ting enzyme activity,` bioassay for the contractile response ofisolated smooth muscle or the pressor response of normal animals and biochemical assay for the enzyme isolated from lung or other organs o animals are known. The former is more useful than the latter for the examination of the conversion of angiotensin I to angiotensin II in vitro (R.L. Soffer, 1976) for the evaluation of the novel compound in the field of mèdicine.
- In the present study, we adopted the bioassay for contractile response of isolated guinea-pig ileum to angiotensin I.
Measurement of inhibitory activity of angiotensin I-converting enzyme Preparation of isolated guinea-pig ileum was made and suspended in the organ bath containing 20 ml of Tyrode;' 5 solution gassed 95% 2 ~ 5~ C2 at 30C. The contraction in-duced by angiotensin I (0.125,ug/ml) given at intervals of 10 minutes was recorded on a recticorder (Nihon Koden) for 90 seconds using FD pick up (ST-lT H, Nihon Koden) The test compounds were added to the bath 5 minutes before the addition of angiotensin I.
The inhibitory activity of angiotensin I-converting ~3~3 1 enzyme was calculated by the following formula:
~ B X 100 A: Contractile intensity of angiotensin I before addition of the compound B: Contractile intensity of angiotensin I after addition of the compound The influence of the compounds on the contractile response o~ isolated guinea-pig ileum to angiotensin II was examined in the same manner as above. Furthert augmentation of the contractile response to bradykinin by the test compounds was studied by the above-mentioned method from the fact that kininase II which destroys bradykinin is thought to be iden~ical with angiotensin I-converting enzyme.
The results are shown in Table 1. The test compounds inhibited the contractile response to angiotensin I but not to angiotensin II tinhibition of angiotensin I-cQnverting enzyme), while they enhanced the response to bradykinin (inhibition of kininase II).
. _ _ . . .. . _ _ The activity of angiotensin I-converting enzyme was measured spectrophotome~ically according to the method of D.W.
Cushman and H.S. Cheung [Biol. Pharmacol., 20, 1637 (1971)].
That is, the absorbance of hippuric acid was measured, which was liberated by incubating hippuryl-L-histidyl-L-leucine ~HHL) as substrate in the presence of angiotensin I-converting anzyme.
Angiotensin I-converting enzyme was extracted from rabbit lung by the method o~ D. ManjuSri and R.L. Soffer [J. Biol. Chem., 250, 6762 (1975)].
Measurement of inhibitory activity of angiotensin I-converting enzyme ~3~43 1 The reaction mixture is as follows:
lOOmM phosphate buffer (pH 8.3) 300mM sodium chloride 5mM HHL
10 4 - 10 8M enzyme inhibitor O-lOmU enzyme 0.25 ml of the above mixture was incubated at 37C for 30 minutes and the reaction was stopped by adding 0.25 ml o~
1 N hydrochloric acid. To this solution, 1.5 ml of ethyl 10 acetate was added in order to extract hippuric acid. 1.0 ml of -~
ethyl acetate layer was collected and evaporated to dryness and the residue ob~ained was dissolved in 1!0 ml o~ water and the absorbance thereof was measured at 228 nm.
The inhibitory activity of angiotensin I-converting enzyme was calculated by the following formula:
Inhibitory percentage = A x 100 - A: Absorbance of the reaction solution without the compound B: Absorbance of the reaction solution in the presence of the compound.
Molar concentration of the compound producing 50% inhibition of angiotensin I-converting enzyme (IC
~ The inhibitory activity o~ the compound was measured at the concentration of 1 x 10 M to 1 x 10 8M and IC50 at each concentration was calculated.
The results are shown in Table 2.
Test compounds are as follows:
Compound A: (4R)-3-~(2S~3-mercapto-2-methyl-propanoyl]-4-thiazolidinecarboxylic acid (the compound of this invention) ~L3~3 1 Compound B: (4R)-3-~(2R)-3-merCap-to-2-methyl-propanoyl]-4-thiazolidi.necarboxylic acid.
Table 1. Inhibitory activity of the compounds against angiotensin I-converting enzyme . _ . . . ~ ~
Compound Final Inhibition Augmentation Inhibition Concentra-tion to A-I to BK to A-II
(M) (%) (~) (~) _ . _ . . _ _ . .. _ . . . _ _ 10-6 7~.6 _ 10-9 _ 22.1 _ _ .
10-5 59.3 _ 0 24.7 A-I : angiotensin I
A-II: angiotensin II
BK : bradykinin _~ _ ~ 3~3~3 .
~ ~ o o ~o ~ o o N C ) rl a) H .
~ ~_ ~
O O QJ
~:X 'X
~ O ~ N
g ,t~ ~1 H tr) r-l ~ ~ . , U~ 1 4 O :
.0 10l l .0 cn ~1 ~
In rl ~ 1,o~ ~:
~i Xi I ri aJ 0~o f) o CO L~
o ~ ` (Ur-l h~D . ::
o a~o :~
O O X ,~ O
O . ~ ~ ~
~ ~ loi o ~ g ~Oi .C ,1 ~ .
.IJ H O U
.,1 ,i ~r I Q~ :, ~C 00 ~
.~ Ln C) l ~0 O r-l 00 h ,i . 0 ~o ~
.,i C', o I l~, H ~ a) O ~ ~q O
. ~ r ~ ~ C~
a) ni ri ~ O o .C~ ~: ~' ~
O ~c0~
~39~3 1 Toxicity test Acute toxicity of the compound of this invention, (4R)-3-~(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acld, is shown in Table 3. As seen in the table, the compound of this invention shows lower toxicity.
(Experimental animals) The male ddy-SLC strain rats (5 weeks of age, weighing 20-25 g) were placed in a breeding room of constant temperature and humidity (24 ~ 1C, 55 + 5%) and fed freely pQllet diet (CE-2, Clea Japan Inc.) and water for a week. The rats showing the normal growth were selected for the experiment.
(Method of administration) 30% suspension or 30% solution (pH 7.0) was administered orally, subcutaneously or intravenously and the toxicity was calculated by the Miller and Tainter method.
Table 3 : LD50 (mg/k~) . .
Route Rats Mice , . . ~
p.o.* 6~00+975 8800~716 (~ lO000**) ~ s.c.** 3650+244 2950+183 i.v.** 3260~234 2300+174 * 30% suspension **30% solution (pH 7.0) It is found from the above pharmacological tests that the compound (I) of this invention is useEul as an antihyperten-sive agent. The compound can be given with the combination of diuretics as other antihypertensive agents. The compound can be administered either orally or parentera~y. The dosage forms are tablet, capsule, granule, powder, suppository, injection, etc.
~IL3~43 1 In the treatment o~ hypertension, these preparations can contain not only general fillers but also antihypertensive agents such as reserpine, ~-methyldopa, guanethidine, clonidine, hydrala~ine, etc. The dosage varies according to symptoms and administration forms, etc. But, usual dosage range is 1 to 5090 mg a day, preferably 10 to 1000 mg once a day or aivided into a few doses.
The following are examples of formulation.
1. Oral drug a. tablet dompound of formula (I) 30 mg lactose 150 mg crystalline cellulose 50 mg calcium carboxymethylcellulose 7 mg magnesium stearate 3 mg Total 240 mg The tablets may be treated with the common film-coating - and further with sugar-coating.
b. granule compound of formula (I) 30 mg ~O polyvinylpyrrolidone 25 mg lactose 385 mg hydroxypropylcellulose 50 mg talc 10 mg Total 500 mg c. powder compound of formula (I)300 mg lactose 230 mg starch 440 my colloidal sllica 30 mg Total 1000 my 1 d. capsule compound of formula (I) 30 mg lactose 102 mg crystalline cellulose 56 mg colloidal silica 2 mg ... . . . ..
Total 19 0 mg
S
CH3 ~ ~ <
~S ~ ~C0~ ~O`H
position comprising of the same. The compound (I) of this inven-tion has an inhibitory acitivity against angiotensin I-converting enzyme and produces a potent antihypertensive action on the renal hypertensive rats. The onset of the compound (I) is rapid after oral administration due to its high lipophilic property. More-over, the compound has less undesirable adverse effects such as enhancement of carragenin-induced edema and of bradykinin-induced nociception in rats.
The compound of this invention is synthesized by the ;
following method.
S-Benzoyl-3-mercapto-2-methylpropanoyl halide represented by the formula (II); C6H5COSCH2CH(CH3)COX wherein X is halogen atom, is reacted with (4R)~thiazolidinecarboxylic acid by a known method such as Schotten-Baumann reaction to obtain (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidine-carboxylic acid. The resulting compound is debenzoylated with heating, if necessary, under the presence of acid or alkali. As ;
the acid for the reaction, inorganic or organic acid such as hydrochloric acid, sulfuric acid, phosphoric zcid and p-toluene-sulfonic acid may be used. As the alkali, hydroxide of alkaline metals and alkaline earth metals such as sodium hydroxide, potassium hydroxide and calcium hydroxide, or ammonia may be used. As the solvent, the organlc solvent or aqueous organic 1 solvent which is not concerned to the reaction may be used. As the solvent which is not concerned to the reaction, lower alcohol such as methanol, ethanol, n-propanol, isopropanol and t-butanol, acetone, tetrahydrofuran, or dioxane may be used. The debenzoylation is well known as ammonolysis in using aqueous ammonia. The reaction is carried out at xoom temperature, with ice-cooling, or with heating. The objective compound is isolated as follows~ The reaction solution containng the objective compound obtained by hyd~olysis is concentrated, iE necessary, cooled and acidified to crystallize the objective compound. If necessary, the compound is extracted with organic solvent such as ethyl acetate, and the organic layer is dehydrated and Concentrated. The obtained compound is purified with the proper solvent such as ethyl acetate and benzene.
EXAMPLE
(4R)-3-[(2S)-3-Mercapto-2-methylpropanoyl]-4-thiazolidine-=- carboxylic acid a) 6.7 g of (4R)-4-thiazolidinecarboxylic acid and 12.6 g of sodium bicarbonate are dissolved in 150 ml of water. To ~his solution, 12.1 g o~ S-benzoyl-3-mercapto-2-methylpropanoyl chloride is added with stirring under ice-coolingO After the addition, the mixture is stirred for 1 hour under ice-cooling and acidified with dilute hydrochloric acid to obtain oil~ The oil is extracted with ethyl acetate,and the ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. To the oil thus obtained, 100 ml of ether is added to obtain crystalsO The crystals are filtered to obtain (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid, yield 5.0 g (29~), mp. 137-139C
(benzene), [~]25 -172.4C (c=l, methanol).
~ ~L3~d~3 Anal. Calc~ for C15H17N04S2: C, 53.08; H, 5.05; N, 4.13.
Found: C, 53.21; H, 5-00; N, 4.19.
Dicyclohexylamine salt mp. 199-200C (ethyl acetate-ethanol) [d]25 -109.9C (c=l~methanol) Anal Calcd. for Cl5Hl7No4s2 C12 23 N, 5.38.
Found: C, 62.32; H, 7.73; N, 5.40.
b) By substituting (2S)-S-benzoyl-3-mercapto-2-methylpropanoyl chloride [[~]25 -37.6 (c=l.0, chloroform)], which is prepared from (2S)-S-benzoyl-3-mercapto-2-methylpropanoic acid [mp.
6~-71C, [~]~5-40.4 lc=2.0, methanol)] and thionyl chloride by known method, for S-benzoyl-3-mercapto-2-methylpropanoyl chloride in the procedure of a~ove a), (4R)-3-[(2S~-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid is obtained, yield 14.1 g (83%), mp. 137-139C (benzene).
: c~ To 2.0 g of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methyl-propanoyl]-4-thiazolidinecarboxylic acid, 20 ml of conc. ammo~ia is added and stirred at room temperature for 1 hour. The excess ammonia is removed by concentration in vacuo and by-product, benzamide, is extracted with ethyl acetate. The water layer is acidified with dilute hydrochloric acid and the produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to obtain (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl~-4-thiazolidinecarboxylic acid, mp. 113-114C
(ether), yield 1.0 g ~72%), [d]25-172.0 (c=l, methanol).
Anal- Calcd- for C8H13N3S2 C~ 40-83; H~ 5-57; N~ 5-95-Found: C, 40. 94; H, 5.54; N, 5.94.
Dicyclohexylamine salt 3~43 1 mp- 190-191C (ethyl aceta-te) [~]25-116.1 (c=l, methanol) Anal- Calcd- for C8H13N3S2 C12H23 Found: C, 57~63; H, 8.70; N, 6.70.
Reference Example a) The filtrate of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methyl-propanoyl]-4-thiazolidinecarboxylic acid in EXAMPIE a) is concentrated to dryness to obtain oil. The oil is applied to silica gel chromatography to obtain (4R)-3-[(2R)-S-benæoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid, yield ~ [o~25 19 5 (c=l, methanol).
Dicyclohexylamine salt mp. 140-141C (ethyl acetate~
[~]D5-53.2O (c=l, methanol).
Anal. Calcd- for ClsH17NO4S2 C12H23 N, 5.38.
:` Found: C, 62.27; H, 7.70; N, 5.36.
b) To 2.0 g of (4R)-3-[(2R)-S-benzoyl-3-mercapto-2-methyl-propanoyl]-4-thiazolidinecarboxylic acid, 20 ml of conc.
ammonia is added and treated in the same manner as mentioned above to obtain (4R)-3-[(2R)-3~mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid, yield 0.8 g (58~), [~]25-81.5 (c=l, methanol).
Dicyclohexylamine salt mp. 179-180C (ethyl acetate-ethanol) [d] 25-84. 5 (c-l, methanol) Anal. Calcd. for C8Hl3No3s2~cl2H23N C,57 66; EII 8-71; N~ 6-72-Found: C, 57.60; H, 8.74; N, 6.70.
The potent antihypertensive effect of the compound and salts of this invention is clear; that is, the inhibitor of ~3~43 1 an~iotensin I-coverting enzyrne which converts biologically inactive decapeptide, angiotensin I, to active octapeptide, angiotensin II, is ~ound to be useful as an antihypertensive medicine~R.L. Soffer, 1976; M.A. Ondetti, et al. 1977). In view of the above, we investigated the pharmacological activities of the present antih~pertènsive agent from the aspect of inhibitory activity against the enzyme.
As the method of measurement of angiotensin I-conver-ting enzyme activity,` bioassay for the contractile response ofisolated smooth muscle or the pressor response of normal animals and biochemical assay for the enzyme isolated from lung or other organs o animals are known. The former is more useful than the latter for the examination of the conversion of angiotensin I to angiotensin II in vitro (R.L. Soffer, 1976) for the evaluation of the novel compound in the field of mèdicine.
- In the present study, we adopted the bioassay for contractile response of isolated guinea-pig ileum to angiotensin I.
Measurement of inhibitory activity of angiotensin I-converting enzyme Preparation of isolated guinea-pig ileum was made and suspended in the organ bath containing 20 ml of Tyrode;' 5 solution gassed 95% 2 ~ 5~ C2 at 30C. The contraction in-duced by angiotensin I (0.125,ug/ml) given at intervals of 10 minutes was recorded on a recticorder (Nihon Koden) for 90 seconds using FD pick up (ST-lT H, Nihon Koden) The test compounds were added to the bath 5 minutes before the addition of angiotensin I.
The inhibitory activity of angiotensin I-converting ~3~3 1 enzyme was calculated by the following formula:
~ B X 100 A: Contractile intensity of angiotensin I before addition of the compound B: Contractile intensity of angiotensin I after addition of the compound The influence of the compounds on the contractile response o~ isolated guinea-pig ileum to angiotensin II was examined in the same manner as above. Furthert augmentation of the contractile response to bradykinin by the test compounds was studied by the above-mentioned method from the fact that kininase II which destroys bradykinin is thought to be iden~ical with angiotensin I-converting enzyme.
The results are shown in Table 1. The test compounds inhibited the contractile response to angiotensin I but not to angiotensin II tinhibition of angiotensin I-cQnverting enzyme), while they enhanced the response to bradykinin (inhibition of kininase II).
. _ _ . . .. . _ _ The activity of angiotensin I-converting enzyme was measured spectrophotome~ically according to the method of D.W.
Cushman and H.S. Cheung [Biol. Pharmacol., 20, 1637 (1971)].
That is, the absorbance of hippuric acid was measured, which was liberated by incubating hippuryl-L-histidyl-L-leucine ~HHL) as substrate in the presence of angiotensin I-converting anzyme.
Angiotensin I-converting enzyme was extracted from rabbit lung by the method o~ D. ManjuSri and R.L. Soffer [J. Biol. Chem., 250, 6762 (1975)].
Measurement of inhibitory activity of angiotensin I-converting enzyme ~3~43 1 The reaction mixture is as follows:
lOOmM phosphate buffer (pH 8.3) 300mM sodium chloride 5mM HHL
10 4 - 10 8M enzyme inhibitor O-lOmU enzyme 0.25 ml of the above mixture was incubated at 37C for 30 minutes and the reaction was stopped by adding 0.25 ml o~
1 N hydrochloric acid. To this solution, 1.5 ml of ethyl 10 acetate was added in order to extract hippuric acid. 1.0 ml of -~
ethyl acetate layer was collected and evaporated to dryness and the residue ob~ained was dissolved in 1!0 ml o~ water and the absorbance thereof was measured at 228 nm.
The inhibitory activity of angiotensin I-converting enzyme was calculated by the following formula:
Inhibitory percentage = A x 100 - A: Absorbance of the reaction solution without the compound B: Absorbance of the reaction solution in the presence of the compound.
Molar concentration of the compound producing 50% inhibition of angiotensin I-converting enzyme (IC
~ The inhibitory activity o~ the compound was measured at the concentration of 1 x 10 M to 1 x 10 8M and IC50 at each concentration was calculated.
The results are shown in Table 2.
Test compounds are as follows:
Compound A: (4R)-3-~(2S~3-mercapto-2-methyl-propanoyl]-4-thiazolidinecarboxylic acid (the compound of this invention) ~L3~3 1 Compound B: (4R)-3-~(2R)-3-merCap-to-2-methyl-propanoyl]-4-thiazolidi.necarboxylic acid.
Table 1. Inhibitory activity of the compounds against angiotensin I-converting enzyme . _ . . . ~ ~
Compound Final Inhibition Augmentation Inhibition Concentra-tion to A-I to BK to A-II
(M) (%) (~) (~) _ . _ . . _ _ . .. _ . . . _ _ 10-6 7~.6 _ 10-9 _ 22.1 _ _ .
10-5 59.3 _ 0 24.7 A-I : angiotensin I
A-II: angiotensin II
BK : bradykinin _~ _ ~ 3~3~3 .
~ ~ o o ~o ~ o o N C ) rl a) H .
~ ~_ ~
O O QJ
~:X 'X
~ O ~ N
g ,t~ ~1 H tr) r-l ~ ~ . , U~ 1 4 O :
.0 10l l .0 cn ~1 ~
In rl ~ 1,o~ ~:
~i Xi I ri aJ 0~o f) o CO L~
o ~ ` (Ur-l h~D . ::
o a~o :~
O O X ,~ O
O . ~ ~ ~
~ ~ loi o ~ g ~Oi .C ,1 ~ .
.IJ H O U
.,1 ,i ~r I Q~ :, ~C 00 ~
.~ Ln C) l ~0 O r-l 00 h ,i . 0 ~o ~
.,i C', o I l~, H ~ a) O ~ ~q O
. ~ r ~ ~ C~
a) ni ri ~ O o .C~ ~: ~' ~
O ~c0~
~39~3 1 Toxicity test Acute toxicity of the compound of this invention, (4R)-3-~(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acld, is shown in Table 3. As seen in the table, the compound of this invention shows lower toxicity.
(Experimental animals) The male ddy-SLC strain rats (5 weeks of age, weighing 20-25 g) were placed in a breeding room of constant temperature and humidity (24 ~ 1C, 55 + 5%) and fed freely pQllet diet (CE-2, Clea Japan Inc.) and water for a week. The rats showing the normal growth were selected for the experiment.
(Method of administration) 30% suspension or 30% solution (pH 7.0) was administered orally, subcutaneously or intravenously and the toxicity was calculated by the Miller and Tainter method.
Table 3 : LD50 (mg/k~) . .
Route Rats Mice , . . ~
p.o.* 6~00+975 8800~716 (~ lO000**) ~ s.c.** 3650+244 2950+183 i.v.** 3260~234 2300+174 * 30% suspension **30% solution (pH 7.0) It is found from the above pharmacological tests that the compound (I) of this invention is useEul as an antihyperten-sive agent. The compound can be given with the combination of diuretics as other antihypertensive agents. The compound can be administered either orally or parentera~y. The dosage forms are tablet, capsule, granule, powder, suppository, injection, etc.
~IL3~43 1 In the treatment o~ hypertension, these preparations can contain not only general fillers but also antihypertensive agents such as reserpine, ~-methyldopa, guanethidine, clonidine, hydrala~ine, etc. The dosage varies according to symptoms and administration forms, etc. But, usual dosage range is 1 to 5090 mg a day, preferably 10 to 1000 mg once a day or aivided into a few doses.
The following are examples of formulation.
1. Oral drug a. tablet dompound of formula (I) 30 mg lactose 150 mg crystalline cellulose 50 mg calcium carboxymethylcellulose 7 mg magnesium stearate 3 mg Total 240 mg The tablets may be treated with the common film-coating - and further with sugar-coating.
b. granule compound of formula (I) 30 mg ~O polyvinylpyrrolidone 25 mg lactose 385 mg hydroxypropylcellulose 50 mg talc 10 mg Total 500 mg c. powder compound of formula (I)300 mg lactose 230 mg starch 440 my colloidal sllica 30 mg Total 1000 my 1 d. capsule compound of formula (I) 30 mg lactose 102 mg crystalline cellulose 56 mg colloidal silica 2 mg ... . . . ..
Total 19 0 mg
2. Injection 1 to 30 mg of compound of formula (I) is contained in 1 ml o~ the aqueous solution (pH 6.5-7.0).
Claims (2)
1. A process for preparing (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid, which comprises treating (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid with acid or alkali.
2. (4R)-3-[(2S)-3-Mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12079477A JPS5455565A (en) | 1977-10-06 | 1977-10-06 | Novel thiazolidine derivative |
| JP120794/77 | 1977-10-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1113943A true CA1113943A (en) | 1981-12-08 |
Family
ID=14795152
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA312,770A Expired CA1113943A (en) | 1977-10-06 | 1978-10-05 | Thiazolidine derivative |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0001978A1 (en) |
| JP (1) | JPS5455565A (en) |
| CA (1) | CA1113943A (en) |
| IT (1) | IT1106924B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2395998A1 (en) * | 1977-06-29 | 1979-01-26 | Yoshitomi Pharmaceutical | NEW THIAZOLIDINE DERIVATIVES AND THEIR APPLICATION IN THE TREATMENT OF HYPERTENSION |
| US4483861A (en) * | 1978-10-31 | 1984-11-20 | Santen Pharmaceutical Co., Ltd. | Antihypertensive sulfur-containing compounds |
| JPS5572169A (en) * | 1978-11-27 | 1980-05-30 | Tanabe Seiyaku Co Ltd | Isoquinoline derivative and its preparation |
| US4692458A (en) * | 1980-03-05 | 1987-09-08 | University Of Miami | Anti-hypertensive agents |
| JPS56139455A (en) * | 1980-04-02 | 1981-10-30 | Santen Pharmaceut Co Ltd | Sulfur-containing acylaminoacid |
| US4399144A (en) * | 1980-04-30 | 1983-08-16 | John Wyeth And Brother Limited | Pyridinium salts |
| WO1997010225A1 (en) * | 1995-09-15 | 1997-03-20 | Smithkline Beecham Plc | Pyrrolidine and thiazole derivatives with antibacterial and metallo-beta-lactamase inhibitory properties |
| EP3754839B1 (en) | 2018-03-29 | 2025-07-09 | Nsk Ltd. | Motor control device and failure detection method for motor control device |
| KR102572378B1 (en) * | 2021-05-20 | 2023-08-31 | 주식회사 원프레딕트 | Diagnosis method for bearing defect using 3 phase motor current signal and apparatus for performing the same |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1559851A (en) * | 1968-01-30 | 1969-03-14 | ||
| CH545068A (en) * | 1968-10-29 | 1973-12-15 | Academia Republicii Socialiste | Means suitable for increasing the body weight of farm animals, process for its production and its use |
| DE2116629A1 (en) * | 1971-04-05 | 1972-10-19 | Institutul de Biochimie, Bukarest | 4-thiazolidinecarboxylic acid derivs - with in vivo thiol liberating activity |
| FR2204411B1 (en) * | 1972-11-02 | 1976-03-05 | Claude Dufour | |
| AU518147B2 (en) * | 1976-12-03 | 1981-09-17 | E.R. Squibb & Sons, Inc. | Derivatives of thiazolidine, thiazine and morpholine carboxylic acids |
-
1977
- 1977-10-06 JP JP12079477A patent/JPS5455565A/en active Granted
-
1978
- 1978-10-04 EP EP78101064A patent/EP0001978A1/en not_active Ceased
- 1978-10-04 IT IT51363/78A patent/IT1106924B/en active
- 1978-10-05 CA CA312,770A patent/CA1113943A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS618043B2 (en) | 1986-03-11 |
| JPS5455565A (en) | 1979-05-02 |
| EP0001978A1 (en) | 1979-05-30 |
| IT1106924B (en) | 1985-11-18 |
| IT7851363A0 (en) | 1978-10-04 |
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